Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many mast cells are present in the tumor tissues of neurofibromatosis 1. We investigated the mechanism of the mast cell increase. Since the stem cell factor (SCF) induces development of mast cells and since the receptor of SCF is encoded by the c-kit gene, we examined the expression of SCF mRNA and c-kit mRNA in neurofibroma tissues. In situ hybridization demonstrated strong expression of c-kit messenger RNA in mast cells in the neurofibroma, but the expression of SCF mRNA was not demonstrable by in situ hybridization in either neurofibroma tissues or control normal skin tissues. When RNA extracted from neurofibroma tissues or normal skin tissues was reverse transcribed and then amplified by the polymerase chain reaction, the amount of SCF cDNA was greater in neurofibroma tissues than in normal skin tissues. The results suggest that SCF and the c-kit receptor are associated with the increase of mast cells in neurofibroma tissues.
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PMID:Possible involvement of c-kit receptor and its ligand in increase of mast cells in neurofibroma tissues. 769 36

We studied 25 cases of schwannoma and 42 cases of neurofibroma immunohistochemically with antibodies to calretinin and S-100 protein to explore the potential usefulness of calretinin in differentiating schwannomas from neurofibromas. Of 25 schwannomas, 24 (96%) showed moderate to strong staining for calretinin, with the extent of staining ranging from focal to diffuse. In contrast, only 3 (7%) of 42 neurofibromas displayed focal weak to moderate staining with calretinin. All 42 cases of neurofibromas and all 25 cases of schwannomas showed diffuse moderate to strong staining with S-100 protein. Calretinin also labeled mast cells, whose presence was confirmed further by staining for c-kit, which commonly was present in both tumor types in a scattered individual cell pattern easily differentiated from the clustered pattern of neoplastic spindle cells. Taken together, these results indicate that calretinin is detected in almost all schwannomas and in only a small percentage of neurofibromas, suggesting it is a useful marker for differentiating schwannomas from neurofibromas. Although mast cells present in these 2 neoplasms also react with calretinin, the pattern of staining can be distinguished easily from that of neoplastic cells.
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PMID:Immunohistochemical staining for calretinin is useful for differentiating schwannomas from neurofibromas. 1548 53

Pigmented neurofibroma (PNF) is a rare variant of neurofibroma showing melanin production. To clarify the clinicopathologic features of PNF and to characterize melanogenesis in PNF, 12 cases of PNF were examined in comparison with schwannoma (SCH, n = 16) and neurofibroma (NF, n = 26). The PNF patients were all Japanese including 7 men and 5 women, and patient age ranged from 11 to 71 years (median, 23.5 years). They showed strong a predisposition for neurofibromatosis type 1. Their tumor size was large, and tumors arose from various sites of skin. Histologically, clusters of epithelioid, dendritic, and spindle melanin-producing cells with faint pigmentation had a tendency to locate in deep dermis and subcutis, which seems to be a characteristic pattern of melanogenesis. There was a transition between melanin-producing cells and Schwann cells. Immunohistochemical examination included known melanogenic markers, microphthalmia-associated transcription factor (MITF), which is a key regulator of melanogenesis, and 2 tyrosine kinase receptors, c-Met and c-Kit, which regulate the development of melanocytes. In PNF, melanin-producing cells were S100 (+), MITF (+), Melan-A (+), tyrosinase (+/-), HMB45 (+/-), c-Met (+), and c-Kit (-). Schwann cells were S100 (+), MITF (-), Melan-A (-), tyrosinase (-), HMB45 (-), c-Met (-), and c-Kit (-), and intermediate spindle cells were S100 (+), MITF (+), Melan-A (+), tyrosinase (-), HMB45 (-), c-Met (+), and c-Kit (-). When compared with SCH and NF, MITF was weakly expressed in a part of tumor cells of SCH, whereas no definite staining was found in NF. c-Met expression was very weak in a scattered manner in SCH (10/15 cases) and NF (10/26 cases). These results suggest that PNF is a unique tumor that shows differentiation toward mature melanin production, but ability of melanin synthesis seems to be impaired. There may be a close relationship between up-regulated MITF and c-Met and the peculiar melanogenic nature of PNF, and both of these are useful diagnostic tools for distinguishing PNFs with less melanin production from NFs.
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PMID:Pigmented neurofibroma: review of Japanese patients with an analysis of melanogenesis demonstrating coexpression of c-met protooncogene and microphthalmia-associated transcription factor. 1611 3

Many mutations of the NF1 gene have been reported in patients with neurofibromatosis type 1 (NF1); however, there have been no documented NF1 gene mutations in Japanese NF1 patients. In the present study, we used the polymerase chain reaction (PCR) and DNA sequencing analysis to characterize the NF1 gene in a 53-year-old Japanese patient with NF1 who suffered from neurofibroma, pheochromocytoma, and gastrointestinal stromal tumor (GIST). Direct sequence analyses revealed a single base substitution in the splicing donor site of intron 6 (IVS6 888+1, G --> A) in one NF1 allele, resulting in an altered splice site (ss) in the mutated allele. Splicing at the cryptic 5' ss in the mutated allele generated mRNA with an insertion of 60 nucleotides. In addition, we screened for mutations in exons 9, 11, 13, and 17 of the c-kit gene in GIST and the succinate dehydrogenase subunit D (SDHD) gene in the pheochromocytoma, but we did not detect any somatic mutations. We report here the first case of an NF1 patient with four neoplasms: neurofibroma, pheochromocytoma, astrocytoma and GIST. Our results suggest that the molecular pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients.
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PMID:Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor. 1674 18

Gastrointestinal stromal tumors are increasingly being recognized because of their characteristic expression of KIT (CD 117). Most KIT-positive gastrointestinal stromal tumors have activating mutations in the c-kit gene. A subgroup of gastrointestinal stromal tumors are negative for KIT expression, and in these tumors, activating mutations in platelet-derived growth factor receptor alpha are common. Most platelet-derived growth factor receptor alpha mutation-positive gastrointestinal stromal tumors show an epithelioid histology and are located in the stomach. Herein, we describe an unusual gastric stromal tumor. The tumor was negative for KIT expression and the morphology did not show an epithelioid pattern but rather was composed of bland spindle cells reminiscent of a neurofibroma. Molecular analysis revealed a somatic mutation in platelet-derived growth factor receptor alpha exon 18 (D842F). Aside from demonstrating a new platelet-derived growth factor receptor alpha mutation, this case illustrates the usefulness of molecular testing as a diagnostic tool and clearly indicates the wide range of morphology that can be observed in gastrointestinal stromal tumors.
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PMID:A gastrointestinal stromal tumor of the stomach morphologically resembling a neurofibroma: demonstration of a novel platelet-derived growth factor receptor alpha exon 18 mutation. 1865 98

Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that Nf1 heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/- hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation.
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PMID:Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. 1898 50

Neurofibromatosis type 1 (NF1) is the most common genetic disorder with a predisposition to malignancy and affects 1 in 3500 persons worldwide. NF1 is caused by a mutation in the NF1 tumor suppressor gene that encodes the protein neurofibromin. Patients with NF1 have cutaneous, diffuse, and plexiform neurofibromas, tumors comprised primarily of Schwann cells, blood vessels, fibroblasts, and mast cells. Studies from human and murine models that closely recapitulate human plexiform neurofibroma formation indicate that tumorigenesis necessitates NF1 loss of heterozygosity in the Schwann cell. In addition, our most recent studies with bone marrow transplantation and pharmacologic experiments implicate haploinsufficiency of Nf1 (Nf1(+/-)) and c-kit signaling in the hematopoietic system as required and sufficient for tumor progression. Here, we review recent studies implicating the hematopoietic system in plexiform neurofibroma genesis, delineate the physiology of stem cell factor-dependent hematopoietic cells and their contribution to the neurofibroma microenvironment, and highlight the application of this research toward the first successful, targeted medical treatment of a patient with a nonresectable and debilitating neurofibroma. Finally, we emphasize the importance of the tumor microenvironment hypothesis, asserting that tumorigenic cells in the neurofibroma do not arise and grow in isolation.
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PMID:Mast cells and the neurofibroma microenvironment. 2023 71

Neurofibromatosis type 1 (NF1) is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene. A second-hit mutation precedes the predominant NF1 neoplasms, which include myeloid leukemia, optic glioma, and plexiform neurofibroma. Despite this requisite NF1 loss of heterozygosity in the tumor cell of origin, nontumorigenic cells contribute to both generalized and specific disease manifestations. In mouse models of plexiform neurofibroma formation, Nf1 haploinsufficient mast cells promote inflammation, accelerating tumor formation and growth. These recruited mast cells, hematopoietic effector cells long known to permeate neurofibroma tissue, mediate key mitogenic signals that contribute to vascular ingrowth, collagen deposition, and tumor growth. Thus, the plexiform neurofibroma microenvironment involves a tumor/stromal interaction with the hematopoietic system that depends, at the molecular level, on a stem cell factor/c-kit-mediated signaling axis. These observations parallel findings in other NF1 disease manifestations and are clearly relevant to medical management of these neurofibromas.
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PMID:Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression. 2207 53

Gastrointestinal neurofibroma usually develops as diffuse gastrointestinal involvement in neurofibromatosis type 1 patients. Only 4 cases of sporadic colonic neurofibroma in a patient without neurofibromatosis type 1 have been reported in the English literature. A 26-year-old female patient underwent colonoscopy, and a 4-cm-sized polypoid mass was identified in the sigmoid colon. Wedge resection of the mass showed a yellowish, hard submucosal tumor. Microscopically, the tumor was composed of wavy spindle cells, fibroblasts, and strands of collagen; the stroma showed scattered myxoid areas. The differential diagnoses included gastrointestinal stromal tumor, schwannoma, and neurofibroma. Immunohistochemistry for c-Kit, DOG (discovered on gastrointestinal stromal tumors)-1, smooth muscle actin, S-100 protein, and CD34 was performed. The tumor cells were diffusely positive for CD34 and S-100 protein, while they were completely negative for c-Kit, DOG-1, and smooth muscle actin. The final diagnosis was neurofibroma. Sporadic colonic neurofibroma is very rare. Given the diffuse positivity for CD34 and its rarity, colonic neurofibroma can be easily misdiagnosed as gastrointestinal stromal tumor. Recognition of this entity would be beneficial for pathologists to avoid misdiagnosis and unnecessary treatment.
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PMID:Neurofibroma of the Colon: A Diagnostic Mimicker of Gastrointestinal Stromal Tumor. 2792 Jun 60

Abdominal ultrasonography revealed a low echoic mass in the upper abdomen of a 65-year-old man. He was referred to our department, where abdominal CT revealed a tumor with a 30-mm contrast effect on the distal side of the inferior part of the duodenum. Endoscopy revealed a submucosal tumor in the same region, and ultrasonic endoscopy showed a low echoic mass with a clear boundary derived from the muscle layer. The duodenum was partially resected based on a diagnosis of suspected gastrointestinal stromal tumors (GIST), and the skin tumor was simultaneously resected. An elastic, soft, 30-mm tumor mass was found in the upper duodenum during surgery, and small nodules of 3-5mm were identified throughout the 110-cm length of the jejunum at intervals of 20-30cm. The histopathological diagnosis was GIST and immunostaining showed the mass to be c-kit and CD34 positive. We diagnosed the skin tumor as a neurofibroma (von Recklinghausen disease). Mutational analysis of c-kit in the resected specimen showed no mutation, therefore suggesting that imatinib would not be effective. Since the nodules remaining in the small intestine might also be GIST, we established a policy of regular imaging assessments.
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PMID:[Case report:multiple gastrointestinal stromal tumors of the small intestine associated with von Recklinghausen disease]. 2988 88


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